title: A non-redundant function of cyclin E1 in hematopoietic stem cells.
abstract: A precise balance between quiescence and proliferation is crucial for the lifelong function of hematopoietic stem cells (HSCs). Cyclins E1 and E2 regulate exit from quiescence in fibroblasts, but their role in HSCs remains unknown. Here, we report a non-redundant role for cyclin E1 in mouse HSCs. A long-term culture-initiating cell (LTC-IC) assay indicated that the loss of cyclin E1, but not E2, compromised the colony-forming activity of primitive hematopoietic progenitors. Ccne1(-/-) mice showed normal hematopoiesis in vivo under homeostatic conditions but a severe impairment following myeloablative stress induced by 5-fluorouracil (5-FU). Under these conditions, Ccne1(-/-) HSCs were less efficient in entering the cell cycle, resulting in decreased hematopoiesis and reduced survival of mutant mice upon weekly 5-FU treatment. The role of cyclin E1 in homeostatic conditions became apparent in aged mice, where HSC quiescence was increased in Ccne1(-/-) animals. On the other hand, loss of cyclin E1 provided HSCs with a competitive advantage in bone marrow serial transplantation assays, suggesting that a partial impairment of cell cycle entry may exert a protective role by preventing premature depletion of the HSC compartment. Our data support a role for cyclin E1 in controlling the exit from quiescence in HSCs. This activity, depending on the physiological context, can either jeopardize or protect the maintenance of hematopoiesis.
authors.affiliation: Center for Genomic Science of IIT@SEMM; Istituto Italiano di Tecnologia (IIT); Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Campaner
authors.forename: Andrea
authors.initials: A
authors.lastname: Viale
authors.forename: Serena
authors.initials: S
authors.lastname: De Fazio
authors.forename: Mirko
authors.initials: M
authors.lastname: Doni
authors.forename: Francesca
authors.initials: F
authors.lastname: De Franco
authors.forename: Luana
authors.initials: L
authors.lastname: D'Artista
authors.forename: Domenico
authors.initials: D
authors.lastname: Sardella
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019927:Cyclin E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology; D005838:Genotype; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D000963:Antimetabolites; D019927:Cyclin E; D015513:Oncogene Proteins; C568314:cyclin E1, mouse; D005472:Fluorouracil